The present invention relates to a pharmaceutical preparation for treating neoplastic conditions, and particularly myeloblastic leukemia.
A variety of antineoplastic agents have been used in the chemotherapeutic treatment of leukemias in humans. Doxorubicin and daunomycin are generally recognized as two of the most effective agents against these diseases. It is postulated that these compounds function by inserting into the DNA complex and thereby prevent replication and division of the neoplasm. Doxorubicin hydrochloride is available from Adria Laboratories, Inc. under the tradename Adriamycin and has been approved for use by the Food and Drug Administration. Specifically, doxorubicin and daunomycin have the formula: ##STR1## with the compound being doxorubicin when R is --OH and daunomycin when R is --H.
Unfortunately, repeated use of doxorubicin and daunomycin is restricted by acute dose-limiting myelosuppression and by chronically dose-limiting cardiotoxicity. Consequently, efforts have been directed to developing more active antineoplastic agents which have fewer of these side effects. The compound of choice would not produce these side effects and would be suitable for frequent administration. Ideally, the compound would also be orally active so that it could be easily administered outside of the hospital setting, possibly by the patient himself.
Many of the efforts to develop preferred antineoplastic agents have centered around derivatives of doxorubicin and daunomycin. Two derivaties which have been found to be more active than their natural analogues are 4-demethoxydaunomycin and 4-demethoxydoxorubicin. These compounds are reported in U.K. Pats. Nos. 1,511,680 and 1,500,421 or 1978. 4-Demethoxydaunorubicin is orally active but highly myelosuppressive. 4-Demethoxydoxorubicin is only modestly potent and is myelosuppressive and orally active.
There are few instances in the literature where N-trifluoroacetyl derivatives of daunomycin or doxorubicin are disclosed as being useful antineoplastic agents. U.S. Pat. No. 4,035,566 to Israel et al discloses pharmaceutical preparations containing N-trifluoroacetyl derivatives of doxorubicin-14-alkanoates and daunomycin-14-alkanoates, but the compounds are not disclosed as being orally active.
Accordingly, there is a need for an orally active antineoplastic agent that is highly active and suitable for frequent administration.